Induction of apoptosis by fenretinide (4HPR) in human ovarian carcinoma cells and its association with retinoic acid receptor expression

✍ Scribed by Rosanna Supino; Mariacristina Crosti; Monica Clerici; Andrea Warlters; Loredana Cleris; Franco Zunino; Franca Formelli

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: French
• Weight: 877 KB
• Volume: 65
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19960208)65:4<491::aid-ijc17>3.0.co;2-d

✦ Synopsis

We previously reported that fenretinide (4HPR) is effective against a human ovarian carcinoma xenografted in nude mice. The effects of 4HPR on ovarian tumors have been further studied in in vitro ovarian carcinoma cell lines A2780, IGROV-I, SW626 and OVCA432. A2780 was the most sensitive line: 50% growth inhibition was obtained after 3 days of exposure to I pM 4HPR, a pharmacologically achievable concentration, whereas approx. 10 pM 4HPR gave a similar inhibition in the other cell lines. All-trans retinoic acid (RA), at doses up to 10 pM, did not inhibit cell proliferation. Gel electrophoresis of DNA from either detached or attached A2780 cells treated with 4HPR revealed DNA ladders in detached cells. Apoptosis was also evidenced in detached 4HPR-treated cells by flow cytometry and microscopic observation. The difference in cell line sensitivity to the anti-proliferative effect of 4HPR was not related to drug uptake or efflux. Only A2780 cells, the most sensitive to 4HPR. expressed constitutive levels of RARP; moreover, the levels of RARa and RARy expression in these cells were higher than in the other cell lines. In A2780 cells, the association of an ICz0 of 4HPR to cisplatin resulted in a strong potentiation of the anti-proliferative effect. These data show (i) that 4HPR, in contrast to RA, has an anti-proliferative effect in human ovarian carcinoma cells which is related to induction of apoptosis and (ii) that among the tested lines, the most responsive to the drug expressed RARP and the highest levels of RARa and RARy. The results also suggest that 4HPR can potentiate the effects of cisplatin in ovarian carcinoma.